| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or health-care-associated pneumonia (HCAP) suspected or confirmed to be due to Gram-positive pathogens. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10035664 |
| E.1.2 | Term | Pneumonia |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the clinical cure rates of the 0.8 mg/kg q12h and 1.2 mg/kg q8h dosing regimens of iclaprim with vancomycin (q12h) in the treatment of patients with hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or health-care associated pneumonia (HCAP) suspected or confirmed to be due to Gram-positive pathogens. |
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| E.2.2 | Secondary objectives of the trial |
To compare the 0.8 mg/kg q12h and 1.2 mg/kg q8h dosing regimens of iclaprim with vancomycin as well as to each other for the following parameters:
- Proportion of patients who had died by Day 28,
- Time to death (censored at Day 28, if alive),
- Proportion of patients with clinical pulmonary infection score (CPIS) of 6 or less approximately 72 hours after start of infusion with study medication (i.e., by Day 4),
- Microbiological outcome at End of Therapy (EOT) and Test of Cure (TOC),
- Safety and tolerability,
- Clinical cure rate (iclaprim q12h versus q8h).
In addition, pharmacokinetic analysis including population pharmacokinetics, will be conducted.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients will be considered for further screening procedures in this study only if they meet both of the following criteria:
1. Suspected or confirmed acute bacterial pneumonia due to Gram-positive pathogens in one of the following subgroups:
- hospital-acquired pneumonia (HAP), i.e., pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission; or
- ventilator-associated pneumonia (VAP), i.e., pneumonia that arises more than 48 hours after endotracheal intubation; or
- healthcare-associated pneumonia (HCAP), i.e., pneumonia diagnosed within 48 hours of hospital admission, in a patient who fulfills at least one of the following criteria:
- hospitalization for at least two days within 90 days of the current infection,
- residence in a nursing home or long-term care facility,
- recipient of intravenous antibiotic therapy, chemotherapy, or wound care within 30 days of the current infection
2. Venous access available for intravenous dosing.
3. At least 2 of the following signs and symptoms typical of acute bacterial pneumonia:
- cough,
- new onset of purulent sputum production or a change (worsening) in character of the sputum,
- auscultatory findings on pulmonary examination of rales and/or pulmonary consolidation (dullness on percussion, bronchial breath sounds, or egophony),
- dyspnea, tachypnea, or hypoxemia with a partial pressure oxygen (PO2) <60 mmHg, particularly if any or all of these are progressive in nature,
- organism consistent with a respiratory pathogen isolated from cultures of respiratory tract, sputum or blood sample; and
- at least 2 of the following signs and symptoms:
- fever (oral temperature >38oC/100.4oF, tympanic temperature >38.5oC/101.2oF, rectal/core temperature >39.0oC/102.2oF) or hypothermia (rectal/core temperature <35oC/95.2oF),
- For non-intubated patients only: respiratory rate >30 breaths per minute,
- pulse rate ≥120 beats per minute (bpm),
- altered mental status,
- leucocytosis with white blood cell (WBC) count >10,000/mm3,
- leucopenia with WBC count <4500/mm3,
- >15% immature neutrophils (bands), regardless of total peripheral WBC count.
4. Pulmonary infiltration consistent with the diagnosis of pneumonia (new or progressive infiltrates, consolidation, or pleural effusion) documented by chest X ray within 48 hours prior to randomization, as interpreted by the radiologist or investigator. The infiltrate must be new, and not likely to be related to another clinical process or condition (for example, congestive heart failure or acute respiratory distress syndrome), as judged by the investigator.
5. Suitable respiratory specimen (sputum/endotracheal specimen or specimen from invasive procedure) for culture, and Gram stain, with indication of Gram-positive pathogens. Average of at least 10 organisms per oil-immersion field in 10 fields (actual or calculated, 100x objective).
For sputum samples, additionally fulfilling both of the following criteria:
- ≤10 squamous epithelial cells, and
- ≥25 leucocytes per low power field (100x) in 10 to 20 fields.
If the above two criteria are not met, a justification should be entered into the CRF.
If the baseline respiratory specimen is obtained by an invasive technique (bronchoscopic or non-bronchoscopic), it is acceptable to obtain the specimen within 24 hours after starting study drug.
6. CPIS >6
7. For females only:
- post-menopausal for at least 1 year, or
- history of hysterectomy or tubal ligation, or
- negative serum pregnancy test (serum -human chronic gonadotropin [-hCG]). If obtaining the serum pregnancy result would cause a delay in treatment, the patient can be entered on the basis of a negative urine pregnancy test result. The urine pregnancy test must be sensitive to at least 50 mU/mL of -hCG, pending results of the serum test. The patient must immediately discontinue study medication if the serum pregnancy test is positive.
8. Informed consent:
If the patient is able to comprehend the scope of the trial:
- written informed consent to participate in the study must be obtained from the patient.
If the patient is unable to comprehend the scope of the trial prior to randomization due to altered mental status associated with the underlying pneumonia:
- written informed consent to participate in the study must be obtained from the patient’s legal representative, as required by national laws, respective regulations and Institutional Review Boards/Independent Ethics Committees/Regional Ethics Boards (IRB/IEC/REB).
(Written informed consent should be sought from the patient as soon as he/she becomes capable of comprehending the scope of the trial.)
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| E.4 | Principal exclusion criteria |
1. APACHE II score <8 or ≥25.
2. Pneumonia not requiring empiric or targeted treatment effective against Gram-positive pathogens.
3. Pulmonary infection due to Gram-positive organisms known to be resistant to either study medication prior to study entry.
4. No requirement for Gram-positive antibiotic coverage based on available culture and Gram stain results.
5. More than 24 hours of prior treatment with vancomycin, linezolid, or other antibiotics effective against Gram-positive pathogens within the 5 days prior to study enrollment.
6. Requirement for empiric treatment for suspected or confirmed concurrent Gram-negative bacterial infection with antibiotics other than aztreonam.
7. Concomitant morbidity of such severity that the patient is likely to die or present with serious medical conditions within 7 days of study entry.
8. Known or suspected pulmonary conditions which are likely to preclude therapeutic response, such as:
- evidence of active tuberculosis or other mycobacterial infections,
- cystic fibrosis,
- bronchial obstruction,
- post-obstructive pneumonia other than chronic obstructive pulmonary disease (COPD),
- known or suspected Pneumocystis jiroveci (Pneumocystis carinii) infection,
- granulomatous disease,
- lung cancer or another malignancy metastatic to the lungs,
- acute respiratory distress syndrome (ARDS).
9. Presence of severe sepsis at the time of entry into the study defined as acute occurrence of non-pulmonary organ dysfunctions or acute worsening of chronic non-pulmonary organ dysfunction within the last 48 hours that is not attributable to an alternative process.
10. Empyema as confirmed by thoracentesis or clearly defined by computed tomography (CT) scan. (Patients with parapneumonic effusions without evidence of empyema may be included.)
11. History of lung transplant or a recent history of bone marrow transplant in post-transplant hospital stay. (Patients with other types of solid organ transplants may be included.)
12. Known or suspected Legionella pneumophila pneumonia.
13. Documented or suspected meningitis, endocarditis, or osteomyelitis.
14. Known or suspected human immunodeficiency virus (HIV) with helper/inducer T lymphocyte (CD4+) count <200 cells/mm3.
15. Immunocompromised, defined as WBC count <1000 cells/mm3 or absolute neutrophil count (ANC) <500 cells/mm3.
16. Current hemodialysis.
17. Body mass index (BMI) <18 or >40 kg/m2.
18. Body weight <34 kg or >133 kg.
19. Any underlying condition or disease that would interfere with the completion of the study procedures or any other condition that in the opinion of the investigator, would confound or interfere with the evaluation of safety or efficacy of the investigational medication, or prevent compliance with the study protocol.
20. Known or suspected hypersensitivity to trimethoprim, iclaprim, or vancomycin, or corresponding excipients.
21. Severe hepatic disease (Child-Pugh Class C), or bilirubin >1.5 x upper limit of normal (ULN) and/or alanine transaminase (ALT) >3 x ULN.
22. Any of the following cardiovascular conditions or risk factors:
- known to have congenital or sporadic syndromes of QTc prolongation,
- concomitant type IA (such as propafenone, flecainide) or III (such as amiodarone, sotalol) anti-arrhythmic drugs,
- nonsustained ventricular tachycardia (NSVT) defined as ≥10 consecutive ventricular beats at a rate of >120 bpm with a duration of <30 sec,
- bradycardia (<50 bpm),
- QT/QTc interval outside the normal range defined as: QTc >470 ms.
23. Severe renal impairment defined as estimated (Cockroft-Gault formula) or known creatinine clearance (CrCL) <30 mL/min.
24. Clinically significant abnormal blood electrolyte levels, which cannot be corrected prior to enrollment:
- potassium ≤3 mmol/L, or,
- magnesium ≤0.5 mmol/L (1.2 mg/dL),
25. Pregnant or lactating female.
26. Age less than 18 years.
27. Unwillingness to be cooperative with the study requirements.
28. Previous enrollment in any iclaprim study.
29. Receipt of any investigational agent or device within 30 days before start of study medication administration.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy: Clinical cure rate at TOC – comparison of the two iclaprim dosing regimens (0.8 mg/kg q12h and 1.2 mg/kg q8h) versus vancomycin (q12h).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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